This proposal will focus on central immunologic, virologic and molecular biologic mechanisms important in the progression and pathogenesis of AIDS. The Program consists of seven interrelated projects and three associated Core facilities which bring together basic and clinical scientists at the Columbia-Presbyterian Medical Center representing the departments of Medicine, Microbiology, Physiology, Biochemistry and Pathology. All of the project leaders are currently involved in basic research efforts highly relevant to AIDS pathogenesis, and the seven proposed projects represent logical extensions of this basic research. Some of the key questions that collectively we will attempt to answer include: (1) Which subsets of cells are initially infected by HIV and provide the cellular reservoir for latent viral infection? (2) Which cellular proteins and receptors in consort with or in lieu of CD4 are involved in viral penetrance and infectivity? (3) What virologic and immunologic mechanisms conspire to activate HIV intracellularly in T4 cells or monocytes and induce the spread of virus? (4) Which HIV genes are crucial for viral penetration, integration and activation? (5) What is the effect of the expression of a variety of HIV genes on the activation and control of cellular genes and cell function? The project leaders in this Program have expertise representing a variety of scientific areas including T cell and macrophage immunobiology and biochemistry, molecular viral pathogenesis, retrovirology and clinical infectious disease. The intent of this Program Project will be to focus the intellectual and technologic resources of these investigators and their disciplines on the solution to the questions outlined above which we feel are essential to understanding AIDS pathogenesis.